U.S. patent application number 16/098428 was filed with the patent office on 2019-04-04 for compositions for the treatment of chronic vulval and perineal pain and symptoms and conditions associated therewith.
This patent application is currently assigned to T & A Pharma Pty Limited. The applicant listed for this patent is T & A Pharma Pty Limited. Invention is credited to Alan HEWITT, Thierry VANCAILLIE.
Application Number | 20190099432 16/098428 |
Document ID | / |
Family ID | 60202529 |
Filed Date | 2019-04-04 |
United States Patent
Application |
20190099432 |
Kind Code |
A1 |
VANCAILLIE; Thierry ; et
al. |
April 4, 2019 |
COMPOSITIONS FOR THE TREATMENT OF CHRONIC VULVAL AND PERINEAL PAIN
AND SYMPTOMS AND CONDITIONS ASSOCIATED THEREWITH
Abstract
Provides herein are compositions for the treatment of chronic
vulval or perineal pain, and of symptoms or conditions associated
therewith, comprising an estrogen, optionally estriol, and a
tricyclic antidepressant, optionally amitriptyline, formulated for
topical, transdermal or transmucosal administration. Also provided
are methods for the production of said compositions and to uses
thereof in the treatment of chronic vulval or perineal pain, and of
symptoms or conditions associated therewith.
Inventors: |
VANCAILLIE; Thierry;
(Castlecrag, AU) ; HEWITT; Alan; (Wrexham,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
T & A Pharma Pty Limited |
Castlecrag, New South Wales |
|
AU |
|
|
Assignee: |
T & A Pharma Pty
Limited
Castlecrag, New South Wales
AU
|
Family ID: |
60202529 |
Appl. No.: |
16/098428 |
Filed: |
May 1, 2017 |
PCT Filed: |
May 1, 2017 |
PCT NO: |
PCT/AU2017/050398 |
371 Date: |
November 1, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/135 20130101;
A61K 31/565 20130101; A61K 31/566 20130101; A61K 45/06 20130101;
A61K 47/14 20130101; A61K 31/567 20130101; A61K 9/0014 20130101;
A61K 47/32 20130101; A61P 15/00 20180101; A61K 2300/00 20130101;
A61K 31/567 20130101; A61K 9/06 20130101; A61K 2300/00 20130101;
A61K 9/107 20130101; A61K 2300/00 20130101; A61K 31/135 20130101;
A61K 47/24 20130101; A61K 47/183 20130101; A61K 31/55 20130101;
A61K 31/565 20130101; A61K 31/55 20130101; A61K 47/46 20130101;
A61K 47/34 20130101; A61K 2300/00 20130101; A61K 31/566 20130101;
A61K 2300/00 20130101 |
International
Class: |
A61K 31/565 20060101
A61K031/565; A61K 31/135 20060101 A61K031/135; A61K 9/00 20060101
A61K009/00; A61K 9/06 20060101 A61K009/06 |
Foreign Application Data
Date |
Code |
Application Number |
May 2, 2016 |
AU |
2016901605 |
Claims
1. A composition for the treatment of chronic vulval or perineal
pain or a symptom or condition associated therewith, the
composition comprising an estrogen and a tricyclic antidepressant,
wherein the composition is formulated for topical, transdermal or
transmucosal administration.
2. A composition according to claim 1, wherein the estrogen is a
natural or synthetic estrogen.
3. A composition according to claim 1 or 2, wherein the estrogen is
selected from the group consisting of estriol, estrone, 17
beta-estradiol, estradiol, estradiol benzoate, estradiol 17
beta-cypionate, ethinyl estradiol, mestranol, moxestrol,
mytatrienediol, polyestradiol phosphate, quinestradiol, quinestrol,
and any combination thereof.
4. A composition according to any one of claims 1 to 3, wherein the
estrogen displays weak estrogenic activity.
5. A composition according to claim 4, wherein the estrogen is
estriol.
6. A composition according to any one of claims 1 to 5, wherein the
tricyclic antidepressant is selected from amitriptyline,
nortriptyline and desipramine.
7. A composition according to any one of claims 1 to 6, wherein the
tricyclic antidepressant is amitriptyline.
8. A composition according to any one of claims 1 to 7, wherein the
composition is a topical composition.
9. A composition according to any one of claims 1 to 8, wherein the
composition is in the form of a gel.
10. A composition according to any one of claims 1 to 9, wherein
the composition is produced using a mixture of an organic phase and
an aqueous phase.
11. A composition according to claim 10, wherein the organic phase
comprises the estrogen, optionally the estriol, and the aqueous
phase comprises the tricyclic antidepressant, optionally
amitriptyline.
12. A composition according to any one of claims 1 to 11, wherein
the condition is vulvodynia or pudendal neuralgia, or a symptom
associated therewith.
13. A composition according to any one of claims 1 to 12, wherein
the condition is selected from vulval vestibulitis, localized
provoked vestibulodynia (LPV), dysesthetic vulvodynia, vulvar
dermatoses or cyclic vulvovaginitis.
14. A composition according to any one of claims 1 to 13, wherein
the condition or symptom associated with chronic vulval or perineal
pain comprises urethritis, urinary frequency or urgency, or faecal
frequency or urgency.
15. A topical composition for the treatment of chronic vulval or
perineal pain or a symptom or condition associated therewith, the
composition comprising estriol and amitriptyline.
16. A method for the treatment of chronic vulval or perineal pain
or a symptom or condition associated therewith, the method
comprising topically, transdermally or transmucosally administering
to a female subject in need thereof a composition according to any
one of claims 1 to 15.
17. A method according to claim 16, wherein the condition is
vulvodynia or pudendal neuralgia, or a symptom associated
therewith.
18. A method according to claim 16 or 17, wherein the condition is
selected from vulval vestibulitis, localized provoked
vestibulodynia (LPV), dysesthetic vulvodynia, vulvar dermatoses or
cyclic vulvovaginitis.
19. A method according to any one of claims 16 to 18, wherein the
condition or symptom associated with chronic vulval or perineal
pain comprises urethritis, urinary frequency or urgency, or faecal
frequency or urgency.
20. A method according to any one of claims 16 to 19, wherein the
composition is a topical composition.
21. A method according to any one of claims 16 to 20, wherein the
composition is a gel.
22. A method for the treatment of chronic vulval or perineal pain
or a symptom or condition associated therewith, the method
comprising topically administering to a female subject in need
thereof a composition comprising estriol and amitriptyline.
23. Use of an estrogen and a tricyclic antidepressant for the
manufacture of a composition for the treatment of chronic vulval or
perineal pain or a symptom or condition associated therewith,
wherein the composition is formulated for topical, transdermal or
transmucosal administration.
24. Use of estriol and amitriptyline for the manufacture of a
composition for the treatment of chronic vulval or perineal pain or
a symptom or condition associated therewith, wherein the
composition is formulated for topical administration.
Description
TECHNICAL FIELD
[0001] The present invention relates generally to compositions and
methods for the treatment of chronic vulval and perineal pain.
Compositions of the invention are formulated for topical,
transdermal or transmucosal delivery and comprise an estrogen,
typically estriol, and a tricyclic antidepressant, typically
amitriptyline.
BACKGROUND OF THE INVENTION
[0002] Vulvodynia is a complex gynaecological disorder
characterised by chronic pain localized to the vulva. It is a
potentially debilitating condition that can last for years, cause
physical disability, sexual dysfunction, and psychological
difficulties. Daily activities and quality of life can be
significantly impaired with many sufferers experiencing difficulty
walking or sitting for long periods, sensitivity to clothing
touching the vaginal area, and mild to intense pain typically
described as burning, stinging or itching. Although often difficult
to diagnose, it is typically estimated that in excess of 15 percent
of the adult female population in western countries may experience
vulvodynia at some point during their lifetime. It most commonly
affects women of child bearing age.
[0003] The most common form of vulvodynia is vulvar vestibulitis.
Women with vulvar vestibulitis typically experience pain involving
and limited to the vestibule and only during or after touch or
pressure is applied. Vulvar vestibulitis is characterized by pain,
tenderness, vestibular erythema, itching, swelling and urethritis.
The pain may be described as sharp, burning, or a sensation of
rawness. Generalized vulvodynia is characterized by diffuse pain
and/or a burning sensation on or around the vulva, the labia
majora, labia minor, and/or the vestibule. The pain can be constant
or intermittent and the symptoms, although not necessarily caused
by touch or pressure to the vulva, can be exacerbated by physical
contact to the area.
[0004] The etiology of vulvodynia is unknown. However, it has been
hypothesized that viral, fungal and bacterial assaults, allergic
reactions, neuropathic processes and an autoimmune response may
play a role. Irritation of the muscles that support the uterus,
bladder and rectum (pelvic floor muscle or levator ani myalgia) as
well as irritation of the nerves of the vulval tissue, known as
pudendal neuralgia, may result in additional painful symptoms
associated with vulvodynia.
[0005] Pudendal neuralgia (or also known as chronic perineal pain)
is a term referring to chronic pain within the distribution of the
pudendal nerve, which comprises the vulva as well as the labia
majora and the skin around the anus as well as part of the mons
veneris. The pudendal nerve also innervates the urethra and the
anal mucosa. Thus the dysfunction of the pudendal nerve extends not
only to the sensory function of the perineal skin (including the
vulva) but also to voiding and defecation. Symptoms such as the
constant urge to void or the sensation of a foreign body in the
rectum can occur. These symptoms are not classified as pain per se
but nevertheless contribute to the individual's disability.
[0006] Because of the potential for multiple causes, chronic pain
such as pudendal neuralgia and vulvodynia can be difficult to
treat. First-line therapy typically involves the treatment of
suspected causes by pharmacologic treatment of infections and the
discontinued use of suspected irritants and therapeutic agents that
may contribute to the problem. Oral medications such as
antihistamines, and tricyclic antidepressants, oral supplements
such as calcium citrate, dietary changes and physical therapy, such
as pelvic floor muscle re-education, may provide some symptomatic
relief. More invasive treatments include interferon intra lesional
injections, laser therapy and surgery, however these options are
costly and may be associated with complications such as hematoma,
wound dehiscence and uneven healing. There is no known cure as such
for chronic pain syndromes such as vulvodynia and pudendal
neuralgia.
[0007] There remains a need for the development of cost effective,
simple to use treatment options for the chronic vulval and perineal
pain associated with conditions such as vulvodynia and pudendal
neuralgia.
SUMMARY OF THE INVENTION
[0008] A first aspect of the present invention provides a
composition for the treatment of chronic vulval or perineal pain,
or of a symptom or condition associated therewith, the composition
comprising an estrogen and a tricyclic antidepressant, wherein the
composition is formulated for topical, transdermal or transmucosal
administration.
[0009] In particular embodiments the composition is a topical
composition.
[0010] The composition may, for example, be in the form of a gel,
cream, ointment or lotion.
[0011] The estrogen may be a natural or synthetic estrogen. The
estrogen may be selected from the group consisting of estriol,
estrone, 17 beta-estradiol, estradiol, estradiol benzoate,
estradiol 17 beta-cypionate, ethinyl estradiol, mestranol,
moxestrol, mytatrienediol, polyestradiol phosphate, quinestradiol,
quinestrol, and any combination thereof.
[0012] Typically the estrogen displays weak estrogenic activity. In
particular embodiments the weak estrogen is estriol.
[0013] The tricyclic antidepressant may be selected from
amitriptyline, nortriptyline and desipramine. In particular
embodiments the tricyclic antidepressant is amitriptyline. The
amitriptyline may be in the form of amitriptyline
hydrochloride.
[0014] In exemplary embodiments the composition is a gel
composition, optionally an organogel. The gel composition may be
produced using as two phase system comprising an organic phase and
an aqueous phase. In one embodiment the organic phase comprises a
mixture of lecithin and isopropyl palmitate. In one embodiment the
aqueous phase comprises a poloxamer.
[0015] Typically the estrogen (more typically wherein the estrogen
is estriol) is dissolved or dispersed in the organic phase and the
tricyclic antidepressant (more typically wherein the tricyclic
antidepressant is amitriptyline or amitriptyline hydrochloride) is
dissolved in the aqueous phase.
[0016] Optionally the composition, or at least the organic phase in
a two phase gel system, further comprises a solubilizing agent.
[0017] The condition associated with chronic vulval pain may be
vulvodynia. The vulvodynia may be localized or generalized
vulvodynia. The condition may be selected from vulval vestibulitis,
localized provoked vestibulodynia (LPV), dysesthetic vulvodynia,
vulvar dermatoses, cyclic vulvovaginitis, or pelvic floor tension
myalgia (levator ani myalgia). The condition associated with
chronic perineal pain may be pudendal neuralgia. The symptom or
associated condition may comprise urethritis, urinary frequency or
urgency or faecal frequency or urgency.
[0018] A second aspect of the invention provides a method for the
treatment of chronic vulval or perineal pain, or of a symptom or
condition associated therewith, the method comprising topically,
transdermally or transmucosally administering to a female subject
in need thereof a composition comprising an estrogen and a
tricyclic antidepressant.
[0019] Typically the method comprises the administration of a
composition according to the first aspect.
[0020] A third aspect of the invention provides the use of an
estrogen and a tricyclic antidepressant for the manufacture of a
composition for the treatment of chronic vulval or perineal pain,
or of a symptom or condition associated therewith, wherein the
composition is formulated for topical, transdermal or transmucosal
administration.
[0021] A fourth aspect of the invention provides a topical
composition for the treatment of chronic vulval or perineal pain,
or of a symptom or condition associated therewith, the composition
comprising estriol and amitriptyline.
[0022] The composition may, for example, be in the form of a gel,
cream, ointment or lotion.
[0023] In exemplary embodiments the composition is a gel
composition, optionally an organogel. The gel composition may be
produced using as two phase system comprising an organic phase and
an aqueous phase. In one embodiment the organic phase comprises a
mixture of lecithin and isopropyl palmitate. In one embodiment the
aqueous phase comprises a poloxamer.
[0024] Typically the estrogen (more typically wherein the estrogen
is estriol) is dissolved or dispersed in the organic phase and the
tricyclic antidepressant (more typically wherein the tricyclic
antidepressant is amitriptyline or amitriptyline hydrochloride) is
dissolved in the aqueous phase.
[0025] Optionally the composition, or at least the organic phase in
a two phase gel system, further comprises a solubilizer.
[0026] A fifth aspect of the invention provides a method for the
treatment of chronic vulval or perineal pain, or of a symptom or
condition associated therewith, the method comprising topically
administering to a female subject a composition comprising estriol
and amitriptyline.
[0027] Typically the method comprises the administration of a
composition according to the fourth aspect.
[0028] A sixth aspect of the invention provides the use of estriol
and amitriptyline for the manufacture of a composition for the
treatment of chronic vulval or perineal pain, or of a symptom or
condition associated therewith, wherein the composition is
formulated for topical administration.
DETAILED DESCRIPTION OF THE INVENTION
[0029] In the context of the present specification, the terms "a"
and "an" are used herein to refer to one or to more than one (i.e.
to at least one) of the grammatical object of the article. By way
of example, "an element" means one element or more than one
element.
[0030] In the context of the present specification, the term
"comprising" means "including principally but not necessarily
solely". Furthermore, variations of the word "comprising", such as
"comprise" and "comprises", have correspondingly varied
meanings.
[0031] In the context of the present specification, the term
"about" is understood to refer to a range of values that a person
of skill in the art would consider equivalent to the recited value
in the context of achieving the same function or result.
[0032] The term "associated with" as used in the context of a
condition associated with chronic vulval pain means a condition
that may have as an underlying cause chronic vulval pain, or that
may otherwise be associated, either directly or indirectly, with
chronic vulval pain.
[0033] The term "weak estrogenic activity" as used herein means
that, compared to a more potent estrogenic compound such as
17.beta.-estradiol, the compound displaying weak estrogenic
activity does not stimulate the nuclear receptor effectively. For
example, estriol is an agonist as well as an antagonist of the beta
estrogen receptor, and prevents binding of estradiol, the more
potent human estrogen, to the G protein-coupled estrogen receptor.
For use in accordance with the present invention, compounds with
weak estrogenic activity, will typically have a stimulatory effect
on the mucosa without significant effect on the nucleus, therefore
only minimally stimulating the estrogen receptor positive cells
elsewhere in the body, namely breast and uterus. Thus, compounds
with weak estrogen activity, such as estriol, may have less
unwanted systemic effects and more pronounced, advantageous local
effects than a more potent estrogen, making them particularly
suitable components of compositions of the present invention.
[0034] As used herein the terms "treating" and "treatment" refer to
any and all uses which remedy a condition or one or more symptoms,
or otherwise hinder, retard, or reverse the progression of a
condition or one or more symptoms thereof in any way whatsoever.
Thus the terms "treating" and the like are to be considered in
their broadest context. For example, treatment does not necessarily
imply that a patient is treated until total recovery.
[0035] The present invention provides compositions and methods for
treating chronic vulval and perineal pain, and symptoms and
conditions associated with such pain. More particularly, provided
herein are compositions comprising an estrogen and a tricyclic
antidepressant, wherein the composition is formulated for topical,
transdermal or transmucosal administration. Also provided herein
are methods of treatment of pain and associated symptoms and
conditions as described herein, employing combinations of an
estrogen and a tricyclic antidepressant, by topical, transdermal or
transmucosal administration.
[0036] Methods and compositions of the invention are applicable the
treatment of a variety of conditions and symptoms associated with
chronic vulval and perineal pain including, but not limited to,
vulvodynia, pudendal neuralgia, pelvic floor tension myalgia, the
constant urge to void, or the sensation of a foreign body in the
rectum, urethritis, and the pain associated with any of these
conditions or symptoms. The vulvodynia may be localized or
generalized vulvodynia. The condition may be selected from, for
example, vulval vestibulitis, localized provoked vestibulodynia
(LPV), dysesthetic vulvodynia, vulvar dermatoses or cyclic
vulvovaginitis.
[0037] The estrogen present in the composition may be a natural or
synthetic estrogen. The estrogen may be selected, for example, from
the group consisting of estriol, estrone, 17 beta-estradiol,
estradiol, estradiol benzoate, estradiol 17 beta-cypionate, ethinyl
estradiol, mestranol, moxestrol, mytatrienediol, polyestradiol
phosphate, quinestradiol, quinestrol, and any combination thereof.
Typically the estrogen will display weak estrogenic activity.
Accordingly, in particular exemplary embodiments of the invention
the estrogen is estriol. Those skilled in the art will appreciate
that other active compounds having estrogenic activity, typically
weak estrogenic activity, may be used as an alternative or in
addition. Estriol is a so-called weak estrogen which is
predominantly produced during pregnancy by the placenta and the
fetal liver. Estriol is an agonist as well as an antagonist of the
beta estrogen receptor, and prevents binding of estradiol, the more
potent human estrogen, to the G protein-coupled estrogen receptor.
Estriol has an excellent stimulatory effect on mucosal tissue,
without significant effect on the nucleus. Thus, the use of estriol
is associated with less unwanted systemic effects and enhanced
beneficial local effects than a more potent estrogen.
[0038] The tricyclic antidepressant present in the composition may
be selected, for example, from the group consisting of
amitriptyline, nortriptyline and desipramine. In particular
exemplary embodiments of the invention the tricyclic antidepressant
is amitriptyline. The amitriptyline may be in any form suitable for
topical, transmucosal or transdermal administration, such as
amitriptyline hydrochloride. Those skilled in the art will
appreciate that other tricyclic antidepressants may be used as an
alternative or in addition. The amitriptyline (or equivalent) acts
as a topical anaesthetic when applied directly to a tegument (skin,
mucosa), reducing the sensitivity of the tegument to touch. This is
a pharmacological effect different from that obtained when the
molecule is introduced via the gastro-intestinal tract.
[0039] The estrogen and the tricyclic antidepressant may each be
present in the composition in an amount between about 0.0005% (w/w)
and about 20% (w/w), between about 0.0005% (w/w) and about 10%
(w/w), between about 0.005% (w/w) and about 5% (w/w), between about
0.005% (w/w) and about 3% (w/w), between about 0.005% (w/w) and
about 1% (w/w), or between about 0.005% (w/w) and about 0.5%
(w/w).
[0040] In embodiments in which the tricyclic antidepressant is
amitriptyline, the amitriptyline may be present at about, for
example, 0.05% (w/w), 0.1% (w/w), 0.2% (w/w), 0.3% (w/w), 0.4%
(w/w), 0.5% (w/w), 0.6% (w/w), 0.7% (w/w), 0.8% (w/w), 0.9% (w/w),
1% (w/w), 1.1% (w/w), 1.2% (w/w), 1.3% (w/w), 1.4% (w/w), 1.5%
(w/w), 1.6% (w/w), 1.7% (w/w), 1.8% (w/w), 1.9% (w/w), 2% (w/w),
2.1% (w/w), 2.2% (w/w), 2.3% (w/w), 2.4% (w/w), 2.5% (w/w), 2.6%
(w/w), 2.7% (w/w), 2.8% (w/w), 2.9% (w/w), 3% (w/w), 3.2% (w/w),
3.4% (w/w), 3.6%, 3.8% (w/w) or 4% (w/w). The skilled addressee
will appreciate that the amount of amitriptyline (or other
tricyclic antidepressant) may be varied depending on a variety of
factors including, for example, the subject to be treated (such as
age, other conditions suffered, general health and wellbeing) and
the nature and severity of the pain or condition to be treated.
Such variations are well within the skill of the ordinary person
skilled in the art and may be made without undue burden.
[0041] In embodiments in which the estrogen is estriol, the estriol
may be present at about, for example, 0.01% (w/w), 0.02% (w/w),
0.03% (w/w), 0.04% (w/w), 0.05% (w/w), 0.06% (w/w), 0.07% (w/w),
0.08% (w/w), 0.09% (w/w), 0.1% (w/w), 0.2% (w/w), 0.3% (w/w), 0.4%
(w/w), 0.5% (w/w), 0.6% (w/w), 0.7% (w/w), 0.8% (w/w), 0.9% (w/w),
1% (w/w), 1.2% (w/w), 1.4% (w/w), 1.6% (w/w), 1.8% (w/w), or 2%
(w/w). Alternatively, the estriol may be present at, for example,
between about 100 .mu.g/gm and about 500 .mu.g/gm based on the
weight of the composition. For example the estriol may be present
at about 100 .mu.g/gm, 125 .mu.g/gm, 150 .mu.g/gm, 175 .mu.g/gm,
200 .mu.g/gm, 225 .mu.g/gm, 250 .mu.g/gm, 275 .mu.g/gm, 300
.mu.g/gm, 325 .mu.g/gm, 350 .mu.g/gm, 375 .mu.g/gm, 400 .mu.g/gm,
425 .mu.g/gm, 450 .mu.g/gm, 475 .mu.g/gm, or 500 .mu.g/gm based on
the weight of the composition. The skilled addressee will
appreciate that the amount of estriol (or other estrogen) may be
varied depending on a variety of factors including, for example,
the subject to be treated (such as age, other conditions suffered,
general health and wellbeing) and the nature and severity of the
pain or condition to be treated. Such variations are well within
the skill of the ordinary person skilled in the art and may be made
without undue burden.
[0042] In an exemplary embodiment, a composition of the invention
comprises amitriptyline at about 0.5% (w/w) and estriol at about
300 .mu.g/gm based on the weight of the composition.
[0043] Compositions of the invention may further comprise one or
more additional agents or compounds such as anti-inflammatory
agents, antioxidants, anti-erythema actives, anti-microbial agents,
essential oils, herbal extracts, vitamins, and the like.
[0044] Exemplary anti-inflammatory agents that may be employed
include steroidal and non-steroidal compounds such as those
suitable for topical administration. Suitable steroidal compounds
include clobetasol propionate, betamethasone dipropionate,
halobetasol proprionate, diflorasone diacetate, fluocinonide,
halcinonide, amcinonide, desoximetasone, triamcinolone acetonide,
mometasone furoate, fluticasone propionate, betamethasone
dipropionate, fluocinolone acetonide, hydrocortisone valerate,
hydrocortisone butyrate, flurandrenolide, triamcinolone acetonide,
mometasone furoate, triamcinolone acetonide, fluticasone
propionate, desonide, fluocinolone acetonide, hydrocortisone
valerate, prednicarbate, triamcinolone acetonide, desonide,
hydrocortisone, hydrocortisone aceponate, hydrocortisone buteprate,
methylprednisolone aceponate, mometasone furoate and prednicarbate.
Suitable non-steroidal anti-inflammatory compounds include
indomethacin, ketoprofen, felbinac, diclofenac, ibuprofen,
piroxicam, benzydamin, acetylsalicylic acid, diflunisal, salsalate,
naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin,
loxoprofen, indomethacin, sulindac, etodolac, ketorolac,
diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam,
lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic
acid, tolfenamic acid, firocoxib, and licofelone, semi-synthetic
glycosaminoglycosan ethers, flavanols, flavonoids, isoflavones and
derivatives. Other suitable anti-inflammatories include, for
example, zinc cream or lotion, and vitamin E oil, cream or
lotion.
[0045] Examples of antioxidants include, but are not limited to,
water-soluble antioxidants such as sulfhydryl compounds and their
derivatives (for example sodium metabisulfite and
N-acetyl-cysteine), lipoic acid and dihydrolipoic acid, resveratrol
and lactoferrin. Oil-soluble antioxidants include, but are not
limited to butylated hydroxytoluene, retinoids, tocopherols,
carotenoids, ubiquinone, dimethylmethoxychromanol and
isoquercetin.
[0046] Examples of anti-erythema actives include, but are not
limited to Matricaria recutita extract, Anthemis nobilis extract,
Centella asiatica extract, Crithmum maritimum extract, Gingko
biloba extract, Centaurea cyaneus extract, and extracts from
Euphrasia species.
[0047] Exemplary antimicrobial agents include anti-bacterial,
anti-viral, anti-fungal and anti-protozoal compounds. Examples of
anti-bacterial compounds include, but are not limited to
antibiotics such as erythromycin, spiramycin, clarithromycin,
clindamycin and tretinoin. Examples of anti-viral compounds
include, but are not limited to acyclovir, amantadine, valacyclovir
and rimantadine. Examples of anti-fungal compounds include, but are
not limited to chlorphenesin, clioquinol, haloprogin, undecylenic
acid, tolnaftate, fluconazole, butoconazole, clotrimazole,
econazole, miconazole, terconazole and tioconazole. Examples of
anti-protozoal compounds include, but are not limited to
anti-malarial drugs, spiramycin and clioquinol.
[0048] Essential oils may enhance the emollient and penetration
properties of the composition. Exemplary essential oils include,
but are not limited to lemongrass oil, tea tree oil, thyme oil, and
lavender oil.
[0049] Suitable vitamins include but are not limited to vitamin A,
pro vitamin A, vitamin B.sub.1, vitamin B.sub.2, vitamin B.sub.3,
vitamin B.sub.4, vitamin B.sub.5, vitamin B.sub.6, vitamin
B.sub.12, vitamin D, vitamin D.sub.2, vitamin D.sub.3, tocopherol
(vitamin E), vitamin F and vitamin K.sub.1.
[0050] The compositions may comprise one or more pharmaceutically
acceptable humectants, emollients or preservatives. The inclusion
of humectants and emollients provide a moisturising effect to the
topical compositions when applied repeatedly to the skin thereby
minimising any drying effect that the composition may impart when
applied to sensitive membranes such as around the vagina.
[0051] A wide variety of suitable emollients are known to those
skilled in the art. See for example the International Cosmetic
Ingredient Dictionary and Handbook, Eds. Wenninger and McEwen, The
Cosmetic, Toiletry, and Fragrance Assoc., Washington, D.C.,
7.sup.th Edition, 1997. Emollients useful in the present invention
include, but are not limited to: glycerin, propylene glycol,
sorbitol, sorbitan palmitate, lanolin, lanolin derivatives,
polyethylene glycol (for example PEG300), aloe vera, glucamate DOE
120, allantoin, alginates, monoester salts of sulfosuccinates,
ceramides, and mixtures thereof. Further exemplary moisturisers
include, but are not limited to, cetyl palmitate, castor oil,
jojoba seed oil, grape seed oil, sunflower seed oil, safflower seed
oil, diglycerin, oleic acid, dimethicone copolyol, dextrin, jojoba
esters, panthenol, squalene, coconut oil, cocoa butter, honey,
hydrogenated lecithin, isopropyl isostearate, hydrogenated
vegetable oil, glyceryl distearate, marine exopolysaccharides,
polyfructol, hyaluronic acid, hydrolysed hyaluronic acid,
flavonoids from Salvia sclarea and Citrus aurantiaca, erythritol,
seed extract from Tamarindus indica, and Opuntia ficus-indica
extract.
[0052] Examples of humectants include, but are not limited to
glycerol, sorbitol, polyethylene glycol, mono- and oligomeric
sugars, natural extracts such as quillaia, lactic acid and
urea.
[0053] Examples of preservatives include but are not limited to
benzyl alcohol and parabens.
[0054] Compositions of the invention may be formulated for topical,
transdermal or transmucosal administration. Typically the
compositions are formulated for topical administration. Suitable
pharmaceutically acceptable carriers, diluents, excipients and
adjuvants suitable for topical compositions include demineralised
or distilled water; saline solution; vegetable based oils such as
peanut oil, safflower oil, olive oil, cottonseed oil, maize oil,
sesame oil, arachis oil or coconut oil; silicone oils, including
polysiloxanes, such as methyl polysiloxane, phenyl polysiloxane and
methylphenyl polysolpoxane; volatile silicones; mineral oils such
as liquid paraffin, soft paraffin or squalane; cellulose
derivatives such as methyl cellulose, ethyl cellulose,
carboxymethylcellulose, sodium carboxymethylcellulose or
hydroxypropylmethylcellulose; lower alkanols, for example ethanol
or iso-propanol; lower aralkanols; lower polyalkylene glycols or
lower alkylene glycols, for example polyethylene glycol,
polypropylene glycol, ethylene glycol, propylene glycol,
1,3-butylene glycol or glycerin; fatty acid esters such as
isopropyl palmitate, isopropyl myristate or ethyl oleate;
polyvinylpyrridone; agar; carrageenan; gum tragacanth or gum
acacia, and petroleum jelly. Typically, the carrier or carriers
will form from 10% to 99.9% by weight of the compositions.
[0055] Compositions of the invention may be in any form suitable
for topical, transdermal or transmucosal administration. For
example, the composition may be in the form of a cream, ointment,
lotion, gel, paste, solution, spray or the like. Compositions may
prepared so as to contain liposomes, micelles, and/or
microspheres.
[0056] Ointments, as is well known in the art, are semisolid
preparations that are typically based on petrolatum or other
petroleum derivatives. The specific ointment base to be used, as
will be appreciated by those skilled in the art, is one that will
provide for optimum drug delivery, and, preferably, will provide
for other desired characteristics as well, e.g., emolliency or the
like. Suitable ointment bases are typically grouped into four
classes: oleaginous bases; emulsifiable bases; emulsion bases; and
water-soluble bases. Oleaginous ointment bases include, for
example, vegetable oils, fats obtained from animals, and semisolid
hydrocarbons obtained from petroleum. Emulsifiable ointment bases
contain little or no water and include, for example, hydroxystearin
sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion
ointment bases are either water-in-oil (W/O) emulsions or
oil-in-water (O/W) emulsions, and include, for example, cetyl
alcohol, glyceryl monostearate, lanolin and stearic acid.
Water-soluble ointment bases are prepared from polyethylene glycols
of varying molecular weight.
[0057] Creams, as also well known in the art, are viscous liquids
or semisolid emulsions, either oil-in-water or water-in-oil. Cream
bases are typically water-washable, and contain an oil phase, an
emulsifier and an aqueous phase. The oil phase may be comprised of
petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
The aqueous phase may exceed the oil phase in volume, and generally
contains a humectant. The emulsifier in a cream formulation is
generally a nonionic, anionic, cationic or amphoteric
surfactant.
[0058] Methods for the preparation of suitable ointments and creams
are well known to those skilled in the art, as are methods for the
preparation of lotions, gels, pastes, solutions, sprays and the
like, for example with reference to any one of numerous texts well
known in the field (such as Remington: The Science and Practice of
Pharmacy).
[0059] In particular embodiments, the composition may be in the
form of a water-based gel wherein the gel includes at least one
gelling agent, a solubilising agent and water.
[0060] Gelling agents that may be used in the compositions of the
invention include, but are not limited to: algal extracts, gums,
polysaccharides, starches, pectins, hydrolysed proteins, cellulose
derivatives and polymers comprising pendant carboxylic acid groups,
or esters thereof, polymers comprising pendant anhydrides of
dicarboxylic acid groups and block co-polymers, including
poloxomers, based on ethylene oxide and/or propylene oxide.
[0061] Algal extracts that may be used include, but are not limited
to alginates and carrageenans. Cellulose derivatives that may be
used include, but are not limited to methylcelluloses,
ethylcelluloses hydroxypropylmethylcelluloses,
hydroxyethylcelluloses and carboxymethylcelluloses, which may or
may not be cross-linked. Hydrolysed proteins include but are not
limited to gelatin.
[0062] Polymers comprising pendant carboxylic acid groups may be
homopolymers, copolymers or interpolymers comprising an acrylic
acid backbone, for example carbomers. In one embodiment, the
gelling agent is a polymer of acrylic acid cross-linked with
polyalkenyl ethers or divinyl glycol. In an alternative embodiment,
the gelling agent is a copolymer of acrylic acid and long-chain
alkyl acrylates crosslinked with polyalkenyl ethers, for example
allyl pentaerythritol.
[0063] Carbomers suitable for use in the present invention include,
but are not limited to, those commercially available under the
trade names Carbopol.RTM. (Lubrizol Advanced Materials, Inc.),
Pemulen.RTM. (Lubrizol Advanced Materials, Inc.), Noveon.RTM.
(Lubrizol Advanced Materials, Inc.), Synthalen.RTM. (3V Sigma) and
Hivis Wako.RTM. (Wako Pure Chemicals Co.). Carbomers used in the
present invention may be carbomers having Brookfield viscosities in
the range of about 40,000 to 70,000 mPa.s at 25.degree. C. In one
embodiment, the carbomer may be Carbopol.RTM. 980.
[0064] Block co-polymers based on ethylene oxide and/or propylene
oxide that are suitable for use in the present invention include
those commercially available under the trade name
Pluronic.RTM..
[0065] The amount of gelling agent present in the composition will
depend on the particular gelling agent being used. Typically the
amount of gelling agent present in the composition is between about
between about 0.01% (w/w) and about 50% (w/w), or between about
0.05% (w/w) and about 40% (w/w), or between about 0.05% (w/w) and
about 30% (w/w), or between about 0.05% (w/w) and about 20% (w/w),
or between about 0.05% (w/w) and about 10% (w/w), or between about
0.05% (w/w) and about 5% (w/w), or between about 0.05% (w/w) and
about 3% (w/w), or between about 0.1% (w/w) and about 2% (w/w).
Where a gelling agent sold under the trade name Carbopol.RTM. is
employed, the amount used may be in the range of between about
0.05% (w/w) and about 5% (w/w). Where a gelling agent sold under
the trade name Pluronic.RTM. is employed, the amount used may be in
the range of between about 1% (w/w) and about 30% (w/w).
[0066] In exemplary embodiments the composition is a gel
composition, optionally an organogel. The gel composition may be
produced using as two phase system comprising an organic phase and
an aqueous phase. Typically, as will be understood by those skilled
in the art, blending or mixing of the organic phase and the aqueous
phase until high shear may be required to produce the organogel.
The ratio of the organic phase to the aqueous phase may be between
about 1:5 and about 5:1, such as about 1:5, 1:4, 1:3, 1:2, 1:1,
2:1, 3:1, 4:1 or 5:1. In an exemplary embodiment the ratio of the
organic phase and the aqueous phase may be about 1:2.
[0067] In one embodiment the organic phase comprises a mixture of
lecithin and isopropyl palmitate. The ratio of the lecithin to
isopropyl palmitate in the organic phase may be between about 1:5
and 5:1, between 1:4 and 4:1, between 1:3 to 3:1, between 1:2 and
2:1, or about 1:1. In one embodiment the aqueous phase comprises a
poloxamer, such as, for example Pluronic.RTM. F-127. Those skilled
in the art will appreciate that a range of other poloxamers may be
used without departing from the scope of the invention. The
appropriate constituents of the organic phase and the aqueous phase
can be determined by those skilled in the art without
experimentation.
[0068] Thus, an exemplary two phase system is the Pluronic.RTM.
Lecithin Organogel (PLO) system.
[0069] In an exemplary embodiment the estriol is typically first
dissolved (either fully dissolved or at least partially dissolved)
or dispersed in a suitable solvent, such as propylene glycol prior
to the addition of the organic phase such as the lecithin/isopropyl
palmitate mixture. The ratio of propylene glycol to the
lecithin/isopropyl palmitate mixture may be between about 1:10 and
about 10:1, such as about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3,
1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1. In an
exemplary embodiment, the ratio of propylene glycol to the
lecithin/isopropyl palmitate mixture may be about 4:10.
[0070] In such two phase systems, typically the estrogen (more
typically wherein the estrogen is estriol) is dissolved or
dispersed in the organic phase and the tricyclic antidepressant
(more typically wherein the tricyclic antidepressant is
amitriptyline or amitriptyline hydrochloride) is dissolved in the
aqueous phase.
[0071] Accordingly, also provided herein is a method for producing
a composition comprising an estrogen and a tricyclic
antidepressant, optionally estriol and amitriptyline, comprising:
incorporating the estrogen, optionally estriol, in an organic
phase, wherein the organic phase optionally comprises a mixture of
lecithin and isopropyl palmitate; incorporating the tricyclic
antidepressant, optionally amitriptyline, in an aqueous phase,
wherein the aqueous phase optionally comprises a poloxamer such as
a Pluronic.RTM. poloxamer, and mixing the organic phase and the
aqueous phase, optionally under conditions of high shear, to
produce a gel composition.
[0072] Optionally the composition, or at least the organic phase in
a two phase gel system, further comprises a solubilizing agent.
[0073] The solubilising agent may be selected from the group
consisting of: pyrrolidone or a derivative thereof, castor oil,
polyethoxylated castor oil, diethylene glycol monoethyl ether,
propylene glycol caprylate, propylene glycol mono caprylate, medium
chain glycerides, 2-methacryloxyethylphosphonylcholine,
cyclodextrins and derivatives thereof, lecithin, polysorbates,
PEG-phospholipids, phospholipids, cholesterol-PEG, saturated
polyglycolised C.sub.8-C.sub.10 glycerides. In one exemplary
embodiment, the solubilising agent is a non-alcoholic solubilising
agent, for example pyrrolidone or a derivative thereof. As used
herein, a non-alcoholic solubilising agent means an agent which is
free or substantially free of alcohols, including polyhydric
alcohols. "Substantially free" will be understood to mean less than
about 0.01%, or less than about 0.005%, or less than about 0.001%
of the recited component. In another exemplary embodiment the
solubilising agent is diethylene glycol monoethyl ether.
[0074] The solubilising agent may be present in an amount between
about 1% (w/w) and about 30% (w/w), or between about 1% (w/w) and
about 20% (w/w), or between about 1% (w/w) and about 15% (w/w), or
between about 1% (w/w) and about 10% (w/w). Those skilled in the
art will, by routine trial and experimentation, be able to
determine the amount of solubilising agent required to either
dissolve or substantially solubilise the active agents.
[0075] The compositions may comprise water in an amount between
about 50% (w/w) and about 90% (w/w), or between about 60% (w/w) and
about 80% (w/w).
[0076] It will be appreciated by persons skilled in the art that
numerous variations and/or modifications may be made to the
invention without departing from the spirit or scope of the
invention as broadly described. The present embodiments are,
therefore, to be considered in all respects as illustrative and not
restrictive.
[0077] The invention will now be described in more detail, by way
of illustration only, with respect to the following examples. The
examples are intended to serve to illustrate this invention and
should not be construed as limiting the generality of the
disclosure of the description throughout this specification.
EXAMPLES
Example 1
Exemplary Compositions Comprising Estriol and Amitriptyline
[0078] An exemplary composition contains the following ingredients:
[0079] Amitriptyline [0080] Estriol [0081] Ethylhexyl stearate
[0082] Emulsifying wax [0083] Tocopheryl acetate [0084] Aloe
barbadensis leaf juice. [0085] Disodium EDTA [0086] Sorbitol [0087]
Cyclopentasiloxane [0088] Methylchloroisothiazolinone (and)
Methylisothiazolinone [0089] Water
[0090] The amitriptyline and estriol may be provided in the form of
powders mixed with a base formulation comprising the remaining
ingredients.
Example 2
Preparation of a High Bioavailability Gel Composition Comprising
Estriol and Amitriptyline
[0091] Estriol is essentially insoluble in water (27 mg per litre),
slightly soluble in alcohol (10 mg/ml in ethanol) and soluble in
pyridine (50 mg/ml). Amitriptyline HCL is soluble in water but the
solubility decreases as pH increases (0.9 mg/ml at pH 6.8, and 1000
mg/ml at pH 1.2).
[0092] In an effort to produce a gel composition comprising estriol
and amitriptyline the inventors selected a Carbopol.RTM. polymer as
the gelling agent. Estriol was dissolved in an alcohol/solubiliser
mix (comprising n-butanol, iso propanol, propylene glycol and
diethylene glycol monoethyl ether) sufficient to hold the estriol
in an aqueous solution (first solution) before adding Carbopol.RTM.
980. The second solution contained amitriptyline HCL in a weak
phosphate buffer to control the pH at 5.7. Both solutions were
prepared successfully however when mixed, no gel formed. Gel
formation of the Carbomer range is affected by salt content and
Carbopol.RTM. Ultrez 21 is more resistant to salt than
Carbopol.RTM. 980. However this substitution did not result in gel
formation. Finally the phosphate buffer was removed to reduce the
salt content and triethanolamine was used to neutralise, but this
also did not result in gel formation.
[0093] Pluronic.RTM. F-127 is a difunctional block copolymer
surfactant terminating in primary hydroxyl groups. At higher
concentrations (20%+) it is very fluid at low temperatures (about
5.degree. C.) but when warmed to about 30.degree. C., becomes a non
fluid clear gel. As it was determined that amitriptyline reduces
the gelling properties of Pluronic.RTM. F-127, it was decided that
a two phase organic/aqueous gel system was appropriate,
specifically a pluronic lecithin organogel (PLO) system. The PLO
system uses Pluronic solution as the aqueous phase and a
lecithin/isopropyl palmitate (LIP; in a 1:1 ratio) as the organic
phase. These two phases, when blended under relatively high shear,
produce an organogel.
[0094] For the organic phase, estriol was dissolved/dispersed (did
not produce a clear solution) in propylene glycol then mixed with
LIP. The ratio of propylene glycol to LIP was 4:10. For the aqueos
phase, amitriptyline HCL was dissolved in water, then Pluronic.RTM.
F-127 was added to give a 20% Pluronic solution. The two phases
were mixed using a syringe to syringe transfer method which produce
a relatively high shear mixing. The ratio of organic to aqueous
phases was 1:2. This produced a stable organogel with final
concentrations of 300 mcg/g estriol and 0.5% w/w amitriptyline.
Stability may be increased by the addition of potassium
sorbate.
[0095] To increase the dissolution of the estriol in the organic
phase, and thereby improve bioavailability, a combination of
solubiliser (diethylene glycol monoethyl ether) and propylene
glycol was employed. A 50/50 mix of diethylene glycol monoethyl
ether and propylene glycol resulted in complete dissolution of the
estriol. This was then blended with the LIP to produce the organic
phase. Mixing the organic phase with the aqueous phase again
resulted in a stable organogel.
* * * * *